Genetic Variant CBLIF:c.1192+195_1192+198dupTATA (chr11-59831479-T-TTATA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_005142.3(CBLIF):c.1192+195_1192+198dupTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 207,476 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 27)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

CBLIF
NM_005142.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.898

Publications

0 publications found

Variant links:

Genes affected

CBLIF (HGNC:4268): (cobalamin binding intrinsic factor) This gene is a member of the cobalamin transport protein family. It encodes a glycoprotein secreted by parietal cells of the gastric mucosa and is required for adequate absorption of vitamin B12. Vitamin B12 is necessary for erythrocyte maturation and mutations in this gene may lead to congenital pernicious anemia. [provided by RefSeq, Jul 2008]

CBLIF Gene-Disease associations (from GenCC):

hereditary intrinsic factor deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

CBLIF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00194 (285/146868) while in subpopulation AMR AF = 0.0059 (86/14578). AF 95% confidence interval is 0.00489. There are 1 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005142.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLIF	NM_005142.3	MANE Select	c.1192+195_1192+198dupTATA		intron	N/A	NP_005133.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CBLIF	ENST00000257248.3	TSL:1 MANE Select	c.1192+198_1192+199insTATA	intron	N/A	ENSP00000257248.2	P27352-1
CBLIF	ENST00000525058.5	TSL:2	n.1159+198_1159+199insTATA	intron	N/A	ENSP00000433196.1	E9PM21
CBLIF	ENST00000533067.1	TSL:3	n.51_52insTATA	downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

285

AN:

146812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00354

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00590

Gnomad ASJ

AF:

0.00352

Gnomad EAS

AF:

0.00237

Gnomad SAS

AF:

0.00129

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000302

Gnomad OTH

AF:

0.00297

GnomAD4 exome

AF:

0.000412

AC:

AN:

60608

Hom.:

AF XY:

0.000338

AC XY:

AN XY:

35532

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000510

AC:

AN:

1962

American (AMR)

AF:

0.000805

AC:

AN:

2486

Ashkenazi Jewish (ASJ)

AF:

0.000623

AC:

AN:

1606

East Asian (EAS)

AF:

0.00165

AC:

AN:

3642

South Asian (SAS)

AF:

0.000389

AC:

AN:

2570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.000211

AC:

AN:

42724

Other (OTH)

AF:

0.00144

AC:

AN:

3484

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.313

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00194

AC:

285

AN:

146868

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

136

AN XY:

71512

show subpopulations

African (AFR)

AF:

0.00353

AC:

143

AN:

40520

American (AMR)

AF:

0.00590

AC:

AN:

14578

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

3410

East Asian (EAS)

AF:

0.00238

AC:

AN:

5036

South Asian (SAS)

AF:

0.00129

AC:

AN:

4638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000302

AC:

AN:

66266

Other (OTH)

AF:

0.00296

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000134

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-59831479-TTATATATATATATATA-TTATATATATATATATATATA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over